Azaheterocyclylmethyl derivatives of 7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene as 5-HT1A antagonists

ABSTRACT

Compounds of the formula                    
     are useful for treating the cognitive deficits due to aging, stroke, head trauma, Alzheimer&#39;s disease or other neurodegenerative diseases, or schizophrenia. The compounds of the invention are also useful for the treatment of disorders such as anxiety, aggression and stress, and for the control of various physiological phenomena, such as appetite, thermoregulation, sleep and sexual behavior.

This application claims priority from provisional application Ser. No.60/289,168, filed on May 7, 2001, the entire disclosure of which ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

Recent studies with the selective 5-HT_(1A) antagonist WAY-100635 haveconfirmed a role for 5-HT_(1A) receptors in learning and memory. Carliet. al. (Neuropharmacology (1999), 38(8), 1165-1173) demonstrated thatWAY-100635 prevented the impairment of spatial learning caused byintrahippocampal injection of3-[(R)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), acompetitive NMDA receptor antagonist, in a two-platform spatialdiscrimination task. Boast et. al. (Neurobiol. Learn. Mem. (1999), 71(3)259-271) found that WAY-100635 significantly reduced the cognitiveimpairment induced by the non-competitive NMDA antagonist MK801, asdetermined by the performance of rats trained on a delayed nonmatchingto sample radial arm maze task. Menesis et al. (Neurobiol. Learn. Mem.(1999), 71(2) 207-218) showed that post-training administration ofWAY-100635 reversed the learning deficit induced by scopolamine, acholinergic antagonist, in an autoshaping learning task. New, novel5-HT_(1A) antagonists would be useful for these and other uses.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelcompounds of the formula I:

wherein

R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to sixcarbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms;

R² is hydrogen, halo, trifluoromethyl, amino, mono- or di-alkylamino inwhich each alkyl group has 1 to 6 carbon atoms, alkoxy of one to sixcarbon atoms or alkyl of one to six carbon atoms;

Z is pyrrolidine, piperidine, homopiperidine, morpholine,thiomorpholine,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms;

Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, or thienyl, eachoptionally substituted;

R⁴ is hydroxy, cyano or carboxamido and R⁵ is Ar; or

R⁴ is hydrogen and R⁵ is benzoyl, 1-benzimidazol-2-one,benzoisothiazole, benzisoxazole, each optionally substituted, or—(CH₂)_(m)Q;

m is 0 to 4; and

Q is Ar,

or a pharmaceutically acceptable salt thereof.

It is preferred in some embodiments of the invention that Z is a radicalof formula II or III.

In some preferred embodiments of the invention R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas one to six carbon atoms; R² is hydrogen, trifluoromethyl, amino,mono- or di-alkylamino in which each alkyl group has one to six carbonatoms, or alkyl of one to six carbon atom; and Z is a radical of formulaII. More preferably, R¹ is hydrogen, halo, trifluoromethyl, alkyl of oneto six carbon atoms or alkoxy of one to six carbon atoms; and R² ishydrogen, trifluoromethyl or alkyl of one to six carbon atom.

In other preferred embodiments of the invention R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas one to six carbon atoms; R² is hydrogen, trifluoromethyl, amino,mono- or di-alkylamino in which each alkyl group has one to six carbonatoms, or alkyl of one to six carbon atom; and Z is a radical of formulaIII. More preferably, R¹ is hydrogen, halo, trifluoromethyl, alkyl ofone to six carbon atoms or alkoxy of one to six carbon atoms; and R² ishydrogen, trifluoromethyl or alkyl of one to six carbon atom.

In still other embodiments of the invention, R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas one to six carbon atoms; R² is hydrogen, trifluoromethyl, amino,mono- or di-alkylamino in which each alkyl group has one to six carbonatoms, or alkyl of one to six carbon atom; and Z is a radical of formulaIV, R⁴ is hydroxy and R⁵ is Ar. More preferably, R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one tosix carbon atoms; and R² is hydrogen, trifluoromethyl or alkyl of one tosix carbon atom.

In further embodiments of the invention R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas one to six carbon atoms; R² is hydrogen, trifluoromethyl, amino,mono- or di-alkylamino in which each alkyl group has one to six carbonatoms, or alkyl of one to six carbon atom; Z is a radical of formula IV,R⁴ is hydrogen and R⁵ is benzoyl, 1-benzimidazol-2-one,benzoisothiazole, or benzisoxazole, each optionally substituted, or—(CH₂)_(m)Q. More preferably, R¹ is hydrogen, halo, trifluoromethyl,alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;and R² is hydrogen, trifluoromethyl or alkyl of one to six carbon atom,and m is 0 or 1.

Where a substituent is “substituted” as used herein it may include from1 to 3 substituents selected from hydrogen, halo, cyano, carboxamido,carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms.

This invention relates to both the R and S stereoisomers of the8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene,as well as to mixtures of the R and S stereoisomers. Throughout thisapplication, the name of the product of this invention, where theabsolute configuration of the8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene isnot indicated, is intended to embrace the individual R and S enantiomersas well as mixtures of the two. In some preferred embodiments of thepresent invention the S stereoisomer is preferred.

Where a stereoisomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. Substantially free, asused herein means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,NY, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

Alkyl, as used herein refers to an aliphatic hydrocarbon chain andincludes straight and branched chains such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1to 3 carbon atoms.

Alkanamido as used herein refers to the group R—C(═O)—NH— where R is analkyl group of 1 to 5 carbon atoms.

Alkanoyloxy as used herein refers to the group R—C(═O)—O— where R is analkyl group of 1 to 5 carbon atoms.

Alkanesulfonamido as used herein refers to the group R—S(O)₂—NH— where Ris an alkyl group of 1 to 6 carbon atoms.

Alkoxy as used herein refers to the group R—O— where R is an alkyl groupof 1 to 6 carbon atoms.

Carboxamido, as used herein refers to the group —CO—NH₂.

Carboalkoxy as used herein refers to the group R—O—C(═O)— where R is analkyl group of 1 to 5 carbon atoms.

Halogen (or halo) as used herein refers to chlorine, bromine, fluorineand iodine.

Pharmaceutically acceptable salts are those derived from such organicand inorganic acids as: acetic, lactic, citric, cinnamic, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids.

Specific compounds of the present invention are:

8-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;

1-[1-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinol;

(4-fluorophenyl)(1-[2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthalen-8-ylmethyl]-4-piperidinyl)methanone;

2-methyl-8-{[4-(3-trifluoromethyl)phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene;and

2-methyl-8-(piperidin-1-ylmethyl)-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta-[a]naphthaleneor pharmaceutically acceptable salts thereof.

The8-azaheterocyclylmethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthalenesof the invention are prepared as illustrated below. Specifically, theappropriately substituted nitroguaiacol is alkylated with allyl bromidein the presence of a suitable base such as sodium hydride and thendemethylated by a reagent such as sodium hydroxide. The resulting4-nitro-2-allyloxyphenol is then alkylated with glycidyl tosylate or anepihalohydrin in the presence of a base such as sodium hydride andheated in a high boiling solvent such as mesitylene or xylene to effectboth rearrangement of the allyl group and cyclization of the dioxanring. The resulting primary alcohol is converted to the tosylate byreaction with p-toluenesulfonyl chloride in the presence of a tertiaryamine or pyridine or alternatively to a halide by reaction with carbontetrabromide or carbon tetrachloride in combination withtriphenylphosphine. The allyl side chain is then isomerized by treatmentwith catalytic bis-acetonitrile

palladium (II) chloride in refluxing methylene chloride or benzene andthe nitro group reduced to the aniline with a suitable reducing agentsuch as tin (II) chloride. The aniline is then acylated with theappropriate acyl halide or anhydride and the olefin cleaved to thecorresponding o-amidobenzaldehyde by treatment with catalytic osmiumtetroxide in the presence of sodium periodate. The aldehyde is convertedto the phenol by treatment with meta-chloroperoxybenzoic acid in aBaeyer-Villager reaction and cyclization to the7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthalene is effected bytreatment at reflux with an appropriate dehydrating agent such as anortho ester. Replacement of the tosylate or halide with theappropriately substituted azaheterocycle (Z—H) in some high boilingsolvent such as dimethyl sulfoxide gives the title compounds of theinvention.

Alternatively, the aniline produced by the tin (II) chloride reductiondescribed above may be protected by a suitable protecting group such ascarbobenzoxy (Cbz) before the olefin is cleaved to the aldehyde bytreatment with osmium tetroxide/sodium periodate and the aldehydeconverted to a phenol by the Baeyer-Villager procedure. Deprotection bytreatment with hydrogen over palladium on carbon gives theo-aminophenol, which is cyclized to the7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene by treatmentwith the appropriate ortho ester, carboxylic acid or anhydride.Treatment of the o-aminophenol

with cyanogen bromide or chloride or a suitably substituted carbamoylchloride leads to compounds of the invention in which R² is amino.Treatment of the o-aminophenol with carbonyl diimidazole gives theoxazolone which leads to compounds of the invention in which R² is halovia treatment with an inorganic anhydride such as phosphoryl chloride orbromide, or to compounds of the invention in which R² is alkoxy bytreatment with the appropriate alkylating agent. Replacement of thetosylate with the appropriately substituted azaheterocycle as abovegives the title compounds of the invention.

Compounds of the invention in which R¹ is hydrogen and R² is alkyl aremost conveniently prepared according to the scheme below. Theappropriate 2′,3′,4′-trihydroxyacylphenone is regioselectively alkylatedwith glycidyl tosylate or an epihalohydrin in the presence of a basesuch as sodium carbonate to give the corresponding7-acyl-8-hydroxybenzodioxan-2-methanol. Following conversion of theketone to the oxime by reaction with hydroxylamine hydrochloride andsodium acetate, cyclization to the oxazole is effected by treatment withphosphoryl chloride in the appropriate dimethylalkanoic acid amide. Theresulting7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol isconverted to the tosylate by treatment with p-toluenesulfonyl chloridein pyridine and combined with the appropriate azaheterocycles asdescribed to give the title compounds of the invention.

The guaiacols, 2′,3′,4′-trihydroxyacylphenones and azaheterocyclesappropriate to the above chemistry are known compounds or can beprepared by one schooled in the art. The compounds of the invention maybe resolved into their enantiomers by conventional methods or,preferably, the individual enantiomers may be prepared directly bysubstitution of (2R)-(−)-glycidyl 3-nitrobenzenesulfonate or tosylate(for the S benzodioxan methanamine) or (2S)-(+)-glycidyl3-nitro-benzenesulfonate or tosylate (for the R enantiomer) in place ofepihalohydrin or racemic glycidyl tosylate in the procedures above.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OH-DPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al. J. Neurochem. 44, 1685(1985) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)'s.

Antagonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol. 109: 1120, 1993), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OH-DPAT. The testcompound's maximum inhibitory effect is represented as the I_(max),while its potency is defined by the IC₅₀.

The results of the two standard experimental test procedures describedin the preceding two paragraphs were as follows:

5-HT_(1A) Receptor Affinity 5-HT_(1A) Function Compound KI (nM) IC₅₀(nM) (I_(max)) Example 1 0.93 1055.0 (60.0) Example 2 1.00  2.70 (42.0)Example 3 6.52  47.0 (47.0) Example 4 201.75 — Example 5 39.43  798.0(97.0) Example 6 172.65 —

The compounds of this invention have potent affinity for and antagonistactivity at brain 5-HT_(1A) serotonin receptors. The compounds of theinvention are thus exceedingly interesting the treatment of cognitivedysfunction such as is associated with mild cognitive impairment (MCI))Alzheimer's disease and other dementias including Lewy Body, vascular,and post stroke dementias. Cognitive dysfunction associated withsurgical procedures, traumatic brain injury or stroke may also betreated in accordance with the present invention. Further, compounds ofthe present invention may be useful for the treatment of diseases inwhich cognitive dysfunction is a co-morbidity such as, for example,Parkinson's disease, autism and attention deficit disorders.

Compounds of the present invention are also useful for treatingcognitive deficits due to CNS disorders such as schizophrenia, (andother psychotic disorders such as paranoia and mano-depressive illness).The compounds are also useful for the treatment of disorders related toexcessive serotonergic stimulation such as anxiety (e.g. generalizedanxiety disorders, panic attacks, and obsessive compulsive disorders),aggression and stress. In addition, compounds of the present inventionmay be useful for the treatment of various physiological conditions suchas Tourette's syndrome, migraine, autism, attention deficit disordersand hyperactivity disorders, sleep disorders, social phobias, pain,thermoregulatory disorders, endocrine disorders, urinary incontinence,vasospasm, stroke, eating disorders such as for example obesity,anorexia and bulimia, sexual dysfunction, and the treatment of alcohol,drug and nicotine withdrawal which are known to be, at least in part,under serotonergic influence. Finally, recent clinical trials employingdrug mixtures (e.g. fluoxetine and pindolol) have demonstrated a morerapid onset of antidepressant efficacy for a treatment combining SSRI(serotonin selective reuptake inhibitor) activity and 5HT1A antagonism(Blier and Bergeron, 1995; F Artigas, et al., 1996, M. B. Tome et al.,1997). The compounds of the invention are thus interesting and useful asaugmentation therapy in the treatment of depressive illness.

Thus the present invention provides methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

The present invention also provides methods of augmenting the treatmentof depression by providing a mammal, preferably a human, with anantidepressant amount of a serotonin selective reuptake inhibitor (suchas, but not limited to, sertraline, fluvoxamine, paroxetine,venlafaxine, duloxetine, citalopram, fluoxetine and metabolites thereof)and an amount of a compound of Formula I sufficient to hasten the onsetof antidepressant efficacy.

Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remingtons Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.

Compounds of the present invention may further be provided incombination with an antidepressant amount of a serotonin selectivereuptake inhibitor to increase the onset of antidepressant efficacy.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The amount provided to a patient will vary depending upon what is beingadministered, the purpose of the administration, such as prophylaxis ortherapy, and the state of the patient, the manner of administration, andthe like. In therapeutic applications, compounds of the presentinvention are provided to a patient already suffering from a disease inan amount sufficient to cure or at least partially ameliorate thesymptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age and responsepattern of the patient. Generally, a starting dose is about 10 mg perday with gradual increase in the daily dose to about 200 mg per day, toprovide the desired dosage level in the human.

Provide as used herein means either directly administering a compound orcomposition of the present invention, or administering a prodrug,derivative or analog which will form an equivalent amount of the activecompound or substance within the body.

The present invention includes prodrugs of compounds of Formula I.“Prodrug”, as used herein means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of Formula I.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975).

The following examples illustrate the production of representativecompounds of this invention.

Intermediate 1 3-Allyloxy-4-methoxynitrobenzene

97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolvedin one liter of DMF and 1.5 equivalents of allyl bromide added. Thereaction was heated to 65° C. for two hours, after which time much ofthe dark color had discharged and tlc (1:1 CH₂Cl₂/hexane) indicated lossof starting material. The solvent was concentrated in vacuum and theresidue washed with water. The product was isolated by filtration anddried in a vacuum. This gave 112 g of pale yellow solid. A samplerecrystallized from methanol, gave m.p. 93-94° C.

Intermediate 2 2-Allyloxy-4-nitrophenol

To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueoussodium hydroxide and the mixture was heated to 65° C. The pale yellowsolid 3-allyloxy-4-methoxynitrobenzene prepared above was added inportions over a 30 minute period and then the temperature was raised to95° C. and maintained for 3 hours, after which time the startingmaterial had been consumed. The mixture was allowed to cool and pouredinto a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude buthomogeneous (by tlc 1:1 CH₂Cl₂/hexane) desired product was isolated as alight brown solid by filtration. This material was subsequentlydissolved in 1:1 hexane/methylene chloride and filtered through silicagel to give 68 g of pale yellow solid, which, when recrystallized fromethyl/acetate/hexane, gave m.p. 61-62° C. The aqueous mother liquorsfrom the initial crystallization above were extracted with 2 L of ethylacetate. This was dried over sodium sulfate, filtered and evaporated toa dark oil. Column chromatography on silica with 1:1 CH₂Cl₂/hexane gavean additional 12 g of the title compound as a yellow solid. Elution with2% MeOH in CHCl₃ gave 12 g of a dark oil which slowly crystallized invacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechol.

Intermediate 3 2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane

20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flaskand washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g(0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previousstep. Addition of the phenol was performed in portions under argon.After stirring the mixture for 30 minutes at room temperature underargon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added and themixture heated at 70-75° C. under nitrogen overnight. Upon cooling, theDMF was removed in vacuum and replaced with one liter of methylenechloride. This was washed with 500 mL portions of 2 N HCl, saturatedsodium bicarbonate and saturated brine and dried over sodium sulfate.The mixture was filtered, concentrated to an oil in vacuum and columnchromatographed on silica gel using 1:1 hexane/methylene chloride aseluant. This gave 43 g of product contaminated with traces of the twostarting materials, followed by 21 g of pure product as a pale yellowsolid. The impure material was recrystallized from 1.2 L of 10% ethylacetate/hexane to give 34 g of pure (homogeneous on silica gel tlc with1:1 hexane/methylene chloride)(R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C.).

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.50; H, 5.21; N; 5.43

Intermediate 4(8-Allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol

(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles)prepared as above was heated at 155° C. in mesitylene for 24 hours undernitrogen. Filtration of the black solid which formed gave 1.5 g of verypolar material. Evaporation of the solvent in vacuum followed by columnchromatography on silica gel with methylene chloride as eluant gave 10 gof recovered starting material and 7.5 g of the desired rearranged(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, whichslowly crystallized on standing in vacuum (m.p. 67° C.). The yield basedon recovered starting material is 75%.

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.26; H, 5.20; N, 5.35

Intermediate 5 Toluene-4-sulfonic acid8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester

9.55 g (38.0 mmole) of(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol wasdissolved in 465 mL of pyridine, 29.0 g (152 mmole) of p-toluenesulfonylchloride was added and the mixture stirred at room temperature undernitrogen overnight. Water was then added to quench the excess tosylchloride and the solvent was removed in vacuum and replaced withmethylene chloride. This solution was washed with 2 N HCl, withsaturated sodium bicarbonate, and with saturated brine, and dried overmagnesium sulfate. Filtration, evaporation in vacuum and columnchromatography on silica gel with 1:1 hexane/methylene chloride aseluant gave 12.6 g (92%) of toluene-4-sulfonic acid(R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ylmethyl ester, which slowlycrystallized to a tan solid (m.p. 60-62° C.) upon standing.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.13; H, 4.58; N, 3.44

Intermediate 6{7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of 10.0 g (24.0 mmole) of(R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g ofbis(acetonitrile)dichloropalladium (II) and the mixture was refluxedunder nitrogen for 48 hours. The catalyst was then removed by filtrationand the filtrate concentrated in vacuum to a brown oil. Columnchromatography on silica gel with methylene chloride as eluant gave 7.2g of the title compound as a mixture of E and Z isomers. A sample of{(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106°C.) by evaporation of a pure E isomer-containing fraction.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.12; H, 4.64; N, 3.39

Intermediate 7{7-Amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

10.0 g (24.0 mmole) of{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate and 28.0 g (123 mmole) of stannous chloridedihydrate were combined and heated to 70° C. in ethyl acetate (250 mL)for 6 hours under nitrogen. After cooling to room temperature, thereaction mixture was poured into ice and was made basic with sodiumbicarbonate. It was then extracted with ethyl acetate, washed withbrine, dried over magnesium sulfate, filtered and evaporated to a brownoil. The crude oil was then chromatographed on silica gel with 50%hexane/methylene chloride to remove impurities and the desired productwas eluted with 0.5% methanol/CH₂Cl₂ to give 8.16 g (91%) of the(R)-enantiomer of the title compound as a yellow oil. For analyticalpurposes, 50 mg of the yellow oil was crystallized from ethanol with theaddition of fumaric acid to give the fumarate of the title compound. MS(ESI) m/z 375 (M+H)+.

Elemental Analysis for: C₁₉H₂₁NO₅S.1.00 C₄H₄O₄ Calc'd: C, 56.20; H,5.13; N, 2.85 Found: C, 56.40; H, 4.99; N, 2.91

Intermediate 8{7-{[(Benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of{(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL)was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reactionmixture was stirred under nitrogen for 0.5 hour, then a solution ofN,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL)was added dropwise over a period of 0.5 hour. The mixture was stirred atroom temperature under nitrogen overnight. The reaction was diluted involume to 350 ml and was then washed with 2N HCl (2×100 mL), saturatedsodium bicarbonate (150 mL) and brine (100 mL), dried over magnesiumsulfate, filtered and evaporated to an oil. The crude oil was columnchromatographed on silica gel with 10% ethyl acetate/hexane to removeimpurities and the product eluted with 60% ethyl acetate/hexane to givethe (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%).¹H (CDCl₃) doublet 7.8 δ (2); multiplet 7.4 δ (7 H); doublet 6.7 δ (2H); multiplet 6.0-6.2 δ (2 H); singlet 5.2 δ (2 H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1 H); singlet 2.4 δ (3 H);doublet 1.9 δ (3 H).

Intermediate 9{7-{[(Benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution{(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL)was added OsO₄ (1.65 mL, 0.270 mmole). Then a solution of NaIO₄ (9.45 g,44.2 mmole) in water (100 mL) was added dropwise. The reaction wasstirred at room temperature under nitrogen overnight. Water (250 mL) wasadded to the mixture and it was then extracted with ethyl acetate. Theorganic phase was then washed with brine, dried over magnesium sulfate,filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of thetitle compound as a yellow solid. ¹H (CDCl₃) broad singlet 10.8 δ (1 H);singlet 10.1 δ (1 H); doublet 7.9 δ (1 H); doublet 7.8 δ (2 H);multiplet 7.4 δ (7 H); doublet 7.0 δ (1 H); singlet 5.2 δ (2 H);multiplet 4.5 δ (1 H); multiplet 4.2 δ (3 H); multiplet 4.1 δ (1 H);singlet 2.4 δ (3 H).

Intermediate 10{7-{[(Benzyloxy)carbonyl]amino}-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

A solution of{(2R)-7-{[(benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (4.45 g, 8.95 mmole) in methylene chloride (50mL) was added dropwise to a solution of m-chloroperoxybenzoic acid (6.45g, 22.4 mmole) in methylene chloride (120 mL). The reaction was stirredunder nitrogen overnight. After dilution to 300 mL in volume, it waswashed with saturated sodium bicarbonate (2×200 mL), brine (100 mL),dried over magnesium sulfate, filtered and evaporated to dryness. AH¹NMR spectra was taken of the crude product and it was determined to bethe formate ester. Cleavage was effected by stirring in methanol overbasic alumina overnight. After filtration and evaporation, the productwas purified by column chromatography on silica gel with hexane toremove the impurities, and the product eluted with methylene chloride togive the (R)-enantiomer of the title compound as a yellow oil (1.80 g,40%). ¹H (CDCl₃) doublet 7.8 δ (2 H); multiplet 7.2-7.4 δ (7 H); broadsinglet 7.0 δ (1 H); doublet 6.4 δ (1 H); singlet 5.2 δ (2 H); multiplet4.4 δ (1 H); multiplet 4.2 δ (3 H); multiplet 4.0 δ (1 H); singlet 2.4 δ(3 H).

Intermediate 11[7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate

A mixture of(2R)-7-{[(benzyloxy)carbonyl]amino}-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (1.8 g, 3.7 mmole) and 0.25 g of 10% palladiumon carbon in 200 mL of methanol was treated with 40 psi of hydrogen on aParr shaker for 3 hours. The catalyst was filtered and washed withadditional methanol. The solvent was evaporated in vacuum to yield 1.25g (87%) of the (R)-enantiomer of the hydrochloride hemihydrate of thetitle compound as a beige foam.

Elemental Analysis for: C₁₆H₁₇NO₆S.1.00 HCl.0.5 H₂O Calc'd: C, 48.43; H,4.83; N, 3.53 Found: C, 48.21; H, 4.34; N, 3.58

Intermediate 12 7,8-Dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate

[(2R)-7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methyl-benzenesulfonate hydrochloride (1.05 g, 2.99 mmole) intrimethyl orthoformate (7 mL) was heated to reflux in the presence of0.20 g of p-toluenesulfonic acid for 3 hours. The solvent was removedunder high vacuum to yield a beige solid. The crude product wasrecrystallized from ethanol to give 0.81 g (75%) of the (R)-enantiomerof the title compound, MS (ESI) m/z 361 (M+H)+.

Elemental Analysis for: C₁₇H₁₅NO₅S Calc'd: C, 56.50; H, 4.18; N, 3.88Found: C,56.10; H, 4.37; N, 3.69

Intermediate 131-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone

To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0 mmole) inDMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then theheterogeneous mixture was heated to 70° C. for 3 hours. After removal ofthe solvent in vacuum, the residue was taken into water (800 mL) and wasthen extracted with ethyl acetate (4×300 mL). The combined organiclayers were dried over magnesium sulfate, filtered and evaporate todryness in vacuum. The crude brown oil thus obtained was columnchromatographed on silica gel with 40% hexane/ethyl acetate as eluant togive the (S)-enantiomer of the title compound as a yellow oil whichsolidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.

Elemental Analysis for: C₁₁H₁₂O₅.0.10 H₂O Calc'd: C, 58.46; H, 5.44Found: C, 58.02; H, 5.09

Intermediate 141-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime

A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1ethanol/pyridine (100 mL) was added to a solution of1-[(3S)-5-hydroxy-3-(hydroxy-methyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone(1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to refluxunder nitrogen for 5 hours. Upon cooling, the solvent was removed andreplaced with ethyl acetate. The solution was then washed with water(200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate,filtered and evaporated in vacuum to give 1.89 g (93%) of the(S)-enantiomer of the title compound as a gray solid, m.p. 162° C. MS(ESI) m/z 240 (M+H)+.

Elemental Analysis for: C₁₁H₁₃NO₅.0.35 H₂O Calc'd: C, 53.81; H, 5.62; N,5.71 Found: C, 53.51; H, 5.30; N, 5.58

Intermediate 15[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol

3.03 g (12.6 mmole) of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime was dissolved in a mixture of 1:3N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled inan ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. Thereaction mixture was stirred under nitrogen over a period of 48 hours.It was then added to an ice cold, saturated solution of sodium acetate,extracted with ethyl acetate, dried over magnesium sulfate, filtered andevaporated in vacuum. The resulting crude oil was column chromatographedon silica gel with 60% hexane/ethyl acetate to remove impurities and theproduct eluted with 40% hexane/ethyl acetate. After evaporation of thesolvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the titlecompound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222(M+H)+.

Elemental Analysis for: C₁₁H₁₁NO₄.0.20 H₂O Calc'd: C, 58.77; H, 5.11; N,6.23 Found: C, 58.93; H, 4.91; N, 6.14

Intermediate 16[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl4-methylbenzenesulfonate

To a solution of[(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]-benzoxazol-8-yl]methanol(1.80 g, 8.14 mmole) in methylene chloride (100 mL) was addedp-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooledin an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4mmole) in methylene chloride (20 mL) was then added dropwise, followedby 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution wasallowed to warm to room temperature and was stirred under nitrogenovernight. The reaction was diluted to 500 mL in volume with methylenechloride, then washed with aqueous 2 N HCl (200 mL), with saturatedaqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried overmagnesium sulfate, filtered and evaporated in vacuum to a yellow oil.The crude oil was column chromatographed on silica gel using methylenechloride to remove impurities and 3% methanol/methylene chloride toelute the (R)-enantiomer of the title compound, which becomes a whitesolid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.

Elemental Analysis for: C₁₈H₁₇NO₈S.0.20 H₂O Calc'd: C, 57.04; H, 4.63;N, 3.70 Found: C, 56.75; H, 4.62; N, 3.51

EXAMPLE 18-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-1-phenyl-1,3,8triazaspiro[4.5]decan-4-one

(8R)-7,8-Dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methyl-benzenesulfonate (0.79 g, 2.1 mmole) and1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one (1.46 g, 6.3 mmole) werecombined in 40 mL of DMSO under nitrogen. This solution was heated to75-80° C. under nitrogen for 4 hours. After completion, the reaction wascooled to room temperature and partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The organic phase was washed withbrine, dried over magnesium sulfate and concentrated in vacuum. Thecrude oil was column chromatographed on silica gel using first methylenechloride to remove impurities and then 1% methanol/methylene chloride toelute 0.62 g of the desired free amine. This was recrystallized fromethanol with the addition of 0.20 g of fumaric acid to give 0.40 g ofthe (S)-enantiomer of the title compound as a white solid, m. p. 240° C.

Elemental Analysis for: C₂₄H₂₆N₄O₄.0.50 C₄H₄O₄.0.10 H₂O Calc'd: C,63.17; H, 5.75; N, 11.33 Found: C, 62.98; H, 5.48; N, 11.18

EXAMPLE 21-[1-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and4-(2-keto-1-benzimidazolinyl)-piperidine (0.77 g, 3.54 mmole) werecombined in 10 mL of DMSO under nitrogen. This solution was heated to82° C. under nitrogen for 4 hours. After completion, the reaction wasallowed to cool to room temperature and was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic phase waswashed with brine, dried over sodium sulfate and concentrated in vacuum.The resulting crude oil was column chromatographed on silica gel usingfirst methylene chloride to remove impurities and then 1%methanol/methylene chloride to elute 0.4 g of the (S)-enantiomer of thetitle compound, m.p. 218-220° C.

Elemental Analysis for: C₂₃H₂₄N₄O₄ Calc'd: C, 65.7; H, 5.75; N, 13.32Found: C, 65.47; H, 5.6; N, 13.13

EXAMPLE 31-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinol

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and4-[3-(trifluoromethyl)phenyl]-4-piperidinol (0.84 g, 3.43 mmole) werecombined in 10 mL of DMSO under nitrogen. This solution was heated to80° C. under nitrogen for 4 hours. After completion, the reaction wasallowed to cool to room temperature and was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic phase waswashed with brine, dried over magnesium sulfate and concentrated invacuum. The resulting crude oil was column chromatographed on silica gelusing first methylene chloride to remove impurities and then 1%methanol/methylene chloride to elute 0.33 g of the (S)-enantiomer of thetitle compound, m.p. 148-151° C.

Elemental Analysis for: C₂₃H₂₃F₃N₂O₄ Calc'd: C, 61.6; H, 5.17; N, 6.25Found: C, 61.55; H, 5.06; N, 5.98

EXAMPLE 4 (4-Fluorophenyl)(1-[2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl]-4-piperidinyl)methanone

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.45 g, 1.2 mmole) and4-(4-fluorobenzoyl)piperidine (0.73 g, 3.54 mmole) were combined in 10mL of DMSO under nitrogen. This solution was heated to 80° C. undernitrogen for 4 hours. After completion, the reaction was cooled to roomtemperature and partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic phase was washed with brine, dried overmagnesium sulfate and concentrated in vacuum. The resulting crude oilwas column chromatographed on silica gel using first methylene chlorideto remove impurities and then 1% methanol/methylene chloride to elute0.28 g of the (S)-enantiomer of the title compound. This wasrecrystallized from ethanol with the addition of one equivalent offumaric acid to give 0.30 g of pale yellow solid, m.p. 229-230° C.

Elemental Analysis for: C₂₃H₂₃FN₂O₄.C₄H₄O₄ Calc'd: C, 61.59; H, 5.17; N,5.32 Found: C, 61.27; H, 5; N, 5.23

EXAMPLE 52-Methyl-8-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.40 g, 1.1 mmole) and4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (0.35 g, 1.54mmole) were combined in 5 mL of DMF and 5 ml of THF under nitrogen. Thissolution was refluxed under nitrogen for overnight. After completion,the reaction was cooled to room temperature and partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate. The organicphase was washed with brine, dried over magnesium sulfate andconcentrated in vacuum. The resulting crude oil was columnchromatographed on silica gel using first methylene chloride to removeimpurities and then 1% methanol/methylene chloride to elute the(S)-enantiomer of the title compound. This was recrystallized fromethanol with the addition of one equivalent of fumaric acid to give 80mg of white solid, m.p. 170-173° C.

Elemental Analysis for: C₂₃H₂₁F₃N₂O₃.C₄H₄O₄ Calc'd: C, 59.34; H, 4.61;N, 5.13 Found: C, 59.38; H, 4.41; N, 4.95

EXAMPLE 62-Methyl-8-(piperidin-1-ylmethyl)-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.38 g, 1 mmole) and piperidine 15 ml werecombined and heated at 80° C. under nitrogen for 4 hours. Aftercompletion, piperidine was removed under vacuum and the residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic phase was washed with brine, dried overmagnesium sulfate and concentrated in vacuum. The crude oil was columnchromatographed on silica gel using first methylene chloride to removeimpurities and then 1% methanol/methylene chloride to elute the(S)-enantiomer of the title compound. This was recrystallized fromethanol with the addition of one equivalent of fumaric acid to give 0.24g of white solid, m.p. 109-112° C.

Elemental Analysis for: C₁₆H₂₀N₂O₃.C₄H₄O₄ Calc'd: C, 59.4; H, 5.98; N,6.93 Found: C, 59.02; H, 6.13; N, 6.82

What is claimed is:
 1. A compound of formula I:

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R² is hydrogen, halo, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxyof one to six carbon atoms or alkyl of one to six carbon atoms; Z ispyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms; Ar is phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, or thienyl; R⁴ is hydroxy, cyano orcarboxamido and R⁵ is Ar; or R⁴ is hydrogen and R⁵ is benzoyl,1-benzimidazol-2-onyl, benzoisothiazolyl, benzisoxazolyl, or—(CH₂)_(m)Q; m is 0 to 4; and Q is Ar,

or a pharmaceutically acceptable salt thereof, wherein said phenyl,naphthyl, pyrimidinyl, pyrazinyl, furyl, thienyl, 1-benzimidazol-2-onyl,benzoisothiazolyl, or benzisoxazolyl groups are optionally substitutedwith substituents selected from hydrogen, halo, cyano, carboxamido,carboalkoxy of two to six carbon atoms, trifluoromethyl, alky of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms.
 2. A compound of claim 1wherein Z is a radical of formula II or III.
 3. A compound of claim 1wherein R¹ is hydrogen, halo, trifluoromethyl, alkyl of one to sixcarbon atoms, alkoxy of one to six carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has one to six carbon atoms; R²is hydrogen, trifluoromethyl, amino, mono- or di-alkylamino in whicheach alkyl group has one to six carbon atoms, or alkyl of one to sixcarbon atoms and Z is a radical of formula II.
 4. A compound of claim 3wherein R¹ is hydrogen, halo, trifluoromethyl, alkyl of one to sixcarbon atoms or alkoxy of one to six carbon atoms and R² is hydrogen,trifluoromethyl or alkyl of one to six carbon atoms.
 5. A compound ofclaim 1 wherein R¹ is hydrogen, halo, trifluoromethyl, alkyl of one tosix carbon atoms, alkoxy of one to six carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has one to six carbon atoms; R²is hydrogen, trifluoromethyl, amino, mono- or di-alkylamino in whicheach alkyl group has one to six carbon atoms, or alkyl of one to sixcarbon atoms; Z is a radical of formula III, R⁴ is hydroxy and R⁵ is Ar.6. A compound of claim 5 wherein R¹ is hydrogen, halo, trifluoromethyl,alkyl of one to six carbon atoms or alkoxy of one to six carbon atomsand R² is hydrogen, trifluoromethyl or alkyl of one to six carbon atoms.7. A compound of claim 1 wherein R¹ is hydrogen, halo, trifluoromethyl,alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms,amino, mono- or di-alkylamino in which each alkyl group has one to sixcarbon atoms; R² is hydrogen, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has one to six carbon atoms, oralkyl of one to six carbon atom; Z is a radical of formula III, R⁴ ishydrogen and R⁵ is benzoyl, 1-benzimidazol-2-onyl, benzoisothiazolyl,benzisoxazolyl, each optionally substituted, or —(CH₂)_(m)Q.
 8. Acompound of claim 7 wherein R¹ is hydrogen, halo, trifluoromethyl, alkylof one to six carbon atoms or alkoxy of one to six carbon atoms; R² ishydrogen, trifluoromethyl or alkyl of one to six carbon atoms, and m is0 or
 1. 9. The compound of claim 1 which is8-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneor a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 which is1-[1-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-oneor a pharmaceutically acceptable salt thereof.
 11. The compound of claim1 which is1-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinolor a pharmaceutically acceptable salt thereof.
 12. The compound of claim1 which is(4-fluorophenyl)(1-[2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl]-4-piperidinyl)methanoneor a pharmaceutically acceptable salt thereof.
 13. The compound of claim1 which is2-methyl-8-{[4-(3-trifluoromethyl)phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthaleneor a pharmaceutically acceptable salt thereof.
 14. The compound of claim1 which is2-methyl-8-(piperidin-1-ylmethyl)-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthaleneor a pharmaceutically acceptable salt thereof.
 15. A method of treatinga subject suffering from a condition selected group consisting ofanxiety, aggression and stress which comprises providing to the subjectsuffering from said condition, a therapeutically effective amount of acompound of formula I

wherein R¹ is hydrogen, halo, cyano, caboxamido, carboalkyoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R² is hydrogen, halo, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxyof one to six carbon atoms or alkyl of one to six carbon atoms; Z ispyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms; Ar is phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, or thienyl; R⁴ is hydroxy, cyano orcarboxamido and R⁵ is Ar; or R⁴ is hydrogen and R⁵ is benzoyl,1-benzimidazol-2onyl, benzoisothiazolyl, benzisoxazolyl, or —(CH₂)_(m)Q;m is 0 to 4; and Q is Ar,

or a pharmaceutically acceptable salt thereof, wherein said phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl groups areoptionally substituted with substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.
 16. Themethod of claim 15 wherein the subject is a human.
 17. A method oftreating a subject suffering from a condition selected from the groupconsisting of eating disorders, disorders of thermoregulation, sleepdysfunction and sexual dysfunction which comprises providing to thesubject suffering from said condition, a therapeutically effectiveamount of a compound of formula I:

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R² is hydrogen, halo, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxyof one to six carbon atoms or alkyl of one to six carbon atoms; Z ispyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms; Ar is phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, or thienyl; R⁴ is hydroxy, cyano orcarboxamido and R⁵ is Ar; or R⁴ is hydrogen and R⁵ is benzoyl,1-benzimidazol-2-onyl, benzoisothiazolyl, benzisoxazolyl, or—(CH₂)_(m)Q; m is 0 to 4; and Q is Ar,

or a pharmaceutically acceptable salt thereof; wherein said phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl groups areoptionally substituted with substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.
 18. Themethod of claim 17 wherein the subject is a human.
 19. A method oftreating a subject suffering depression comprising providing to thesubject suffering from said condition, an antidepressant amount of aserotonin selective reuptake inhibitor and an amount of a compound offormula I:

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R² is hydrogen, halo, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxyof one to six carbon atoms or alkyl of one to six carbon atoms; Z ispyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms; Ar is phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, or thienyl; R⁴ is hydroxy, cyano orcarboxamido and R⁵ is Ar; or R⁴ is hydrogen and R⁵ is benzoyl,1-benzimidazol-2-onyl, benzoisothiazolyl, benzisoxazolyl, or—(CH₂)_(m)Q; m is 0 to 4; and Q is Ar,

or a pharmaceutically acceptable salt thereof, wherein said phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl groups areoptionally substituted with substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms. said amountbeing effective to increase the onset of antidepressant efficacy. 20.The method of claim 19 wherein the subject is a human.
 21. The method ofclaim 19 wherein the serotonin selective reuptake inhibitor issertraline, fluvoxamine, paroxetine, venlafaxine, duloxetine,citalopram, fluoxetine or metabolites thereof.
 22. A pharmaceuticalcomposition comprising a compound of formula I:

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R² is hydrogen, halo, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxyof one to six carbon atoms or alkyl of one to six carbon atoms; Z ispyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl,

R³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms or alkynyl or 3 to 6 carbon atoms; Ar is phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, or thienyl; R⁴ is hydroxy, cyano orcarboxamido and R⁵ is Ar; or R⁴ is hydrogen and R⁵ is benzoyl,1-benzimidazol-2-onyl, benzoisothiazolyl, benzisoxazolyl, or—(CH₂)_(m)Q; m is 0 to 4; and Q is Ar,

or a pharmaceutically acceptable salt thereof; wherein said phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl groups areoptionally substituted with substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms. and apharmaceutically acceptable carrier or excipient.
 23. The composition ofclaim 22 further comprising an antidepressant amount of a serotoninselective reuptake inhibitor.
 24. The composition of claim 23 whereinthe serotonin selective reuptake inhibitor is sertraline, fluvoxamine,paroxetine, venlafaxine, duloxetine, citalopram, fluoxetine ormetabolites thereof.
 25. A compound of claim 1 wherein at least one ofsaid phenyl, pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl bears 1 to 3substituents selected from hydrogen, halo, cyano, carboxamido,carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms.
 26. A compound of claim 15wherein at least one of said phenyl, pyridinyl, pyrimidinyl, pyrazinyl,furyl, thienyl, 1-benzimidazol-2-onyl, benzoisothiazoyl, orbenzisoxazoyl bears 1 to 3 substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.
 27. Acompound of claim 17 wherein at least one of said phenyl, pyridinyl,pyrimidinyl, pyrazinyl, furyl, thienyl, 1-benzimidazol-2-onyl,benzoisothiazoyl, or benzisoxazoyl bears 1 to 3 substituents selectedfrom hydrogen, halo, cyano, carboxamido, carboalkoxy of two to sixcarbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms.
 28. A compound of claim 19 wherein at least one of said phenyl,pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl,1-benzimidazol-2-onyl, benzoisothiazoyl, or benzisoxazoyl bears 1 to 3substituents selected from hydrogen, halo, cyano, carboxamido,carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms.
 29. A compound of claim 22wherein at least one of said phenyl, pyridinyl, pyrimidinyl, pyrazinyl,furyl, thienyl, benzoyl, 1-benzimidazol-2-onyl, benzoisothiazoyl, orbenzisoxazoyl bears 1 to 3 substituents selected from hydrogen, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.